Thrombospondins function as regulators of angiogenesis.
Thrombospondins function as regulators of angiogenesis.
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DOI：
10.1007/s12079-009-0060-8
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发表时间：
2009-12
影响因子：
4.1
通讯作者：
Bornstein, Paul
中科院分区：
文献类型：
--
作者：
Bornstein, Paul
关键词：
血小板反应蛋白（TSPs）-1和-2是第一个被鉴定的血管生成蛋白抑制剂，随后将其归因于I型重复序列与内皮细胞表面受体的相互作用。TSPs-1和TSPs-2与细胞表面受体、蛋白酶、生长因子和其他生物活性分子的相互作用，加上不存在可归因于这些基质蛋白的直接结构功能，使它们有资格列入“基质细胞蛋白”的类别。TSP-1、TSP-2和双TSP-1/2缺失小鼠的表型证实了这些蛋白在血管生成调节中的作用，并为这些多结构域蛋白的一些其他重要功能提供了线索。这些功能之一是TSP-1激活潜在TGFβ1复合物的能力，这是TSP-2所不具有的特性。TSP 1或TSP 2抑制血管生成的主要途径涉及与内皮细胞上的CD 36的相互作用，这导致配体和相邻细胞的凋亡。然而，抑制内皮细胞增殖的稳态机制也已得到阐明，并且在某些情况下可能在生理上是优选的，并且涉及与极低密度脂蛋白受体（VLDLR）的相互作用。TSP 1与其受体CD 47的相互作用通过拮抗内皮细胞和血管平滑肌细胞中的一氧化氮信号而进一步抑制血管生成。巧合的是，也有证据表明TSP-1可以起到促进血管生成的作用。这种明显的矛盾可以通过蛋白质的不同结构域中存在与内皮细胞上不同受体相互作用的序列来解释。TSP的抗血管生成功能已经激发了人们对其作为抗肿瘤剂的用途的兴趣。目前，基于已显示具有抗血管生成性质的TSP的I型重复序列的肽模拟物正在进行临床测试。
Thrombospondins (TSPs) -1 and -2 were among the first protein inhibitors of angiogenesis to be identified, a property that was subsequently attributed to the interactions of sequences in their type I repeats with endothelial cell-surface receptors. The interactions of TSPs-1 and -2 with cell-surface receptors, proteases, growth factors, and other bioactive molecules, coupled with the absence of direct structural functions that can be attributed to these matrix proteins, qualify them for inclusion in the category of ‘matricellular proteins’. The phenotypes of TSP-1, TSP-2, and double TSP-1/2-null mice confirm the roles that these proteins play in the regulation of angiogenesis, and provide clues to some of the other important functions of these multi-domain proteins. One of these functions is the ability of TSP-1 to activate the latent TGFβ1 complex, a property that is not shared by TSP-2. A major pathway by which TSP1 or TSP2 inhibits angiogenesis involves an interaction with CD 36 on endothelial cells, which leads to apoptosis of both the liganded and adjacent cells. However a homeostatic mechanism, which inhibits endothelial cell proliferation, and may be physiologically preferable under some circumstances, has also been elucidated, and involves interaction with the very low density lipoprotein receptor (VLDLR). The interaction of TSP1with its receptor, CD47, further inhibits angiogenesis by antagonizing nitric oxide signaling in endothelial and vascular smooth muscle cells. Paradoxically, there is also evidence that TSP-1 can function to promote angiogenesis. This apparent contradiction can be explained by the presence of sequences in different domains of the protein that interact with different receptors on endothelial cells. The anti-angiogenic function of TSPs has spurred interest in their use as anti-tumor agents. Currently, peptide mimetics, based on sequences in the type I repeats of TSPs that have been shown to have anti-angiogenic properties, are undergoing clinical testing.
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DOI：
10.1083/jcb.138.3.707
发表时间：
1997-08-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Dawson DW;Pearce SF;Zhong R;Silverstein RL;Frazier WA;Bouck NP
通讯作者：
Bouck NP
影响因子：
15.9
作者：
Bornstein, P
通讯作者：
Bornstein, P
影响因子：
10.4
作者：
Annis, DS;Murphy-Ullrich, JE;Mosher, DF
通讯作者：
Mosher, DF
影响因子：
45.3
作者：
Baker, Laurence H.;Rowinsky, Eric K.;Demetri, George D.
通讯作者：
Demetri, George D.
影响因子：
11.4
作者：
Blake, Sophia M.;Strasser, Vera;Nimpf, Johannes
通讯作者：
Nimpf, Johannes